Precision medicine in critically ill patients Exploring ARDS and sepsis subphenotypes

This thesis is dedicated to advancing the understanding of sepsis and acute respiratory distress syndrome (ARDS) subphenotypes in critically ill patients, with the overarching goal of addressing key challenges that hinder their clinical implementation. This work aims to clarify the biological and clinical variability within sepsis and ARDS populations. Through this comprehensive exploration, it aspires to bring the science of phenotyping one step closer to the bedside in critical care medicine. In this thesis the role of plasma protein biomarkers in identifying biological heterogeneity among COVID-19 patients is investigated. While previous studies assumed significant heterogeneity in COVID-19, analysis of hospitalized patients found limited support for distinct subphenotypes. Further investigation into treatment heterogeneity in severe COVID-19 revealed that vilobelimab, a C5a inhibitor, showed a survival benefit only in patients classified under a predefined sepsis δ-subtype, underscoring the potential of predictive enrichment strategies. In sepsis, multiple subtyping methods were examined, revealing limited overlap between classifications based on clinical, biomarker, and transcriptomic data. However, biomarker-based subtypes appeared to bridge clinical and molecular classifications. The dynamic nature of subphenotypes was further explored, showing frequent transitions over time, with shifts to less inflammatory states associated with improved outcomes. At ICU discharge, an inflammatory profile was linked to higher long-term mortality. Finally, distinct mortality predictors were identified, suggesting modifiable risk factors in Hyperinflammatory patients and emphasizing the need for tailored therapeutic approaches.